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Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

ABSTRACT: Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16^Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16^Ink4a -positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16^Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions' being a potential therapeutic avenue for alleviating age-associated cognitive impairment.

SUBMITTER: Ogrodnik M

PROVIDER: S-EPMC7884042 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

Ogrodnik Mikolaj M Evans Shane A SA Fielder Edward E Victorelli Stella S Kruger Patrick P Salmonowicz Hanna H Weigand Bettina M BM Patel Ayush D AD Pirtskhalava Tamar T Inman Christine L CL Johnson Kurt O KO Dickinson Stephanie L SL Rocha Azucena A Schafer Marissa J MJ Zhu Yi Y Allison David B DB von Zglinicki Thomas T LeBrasseur Nathan K NK Tchkonia Tamar T Neretti Nicola N Passos João F JF Kirkland James L JL Jurk Diana D

Aging cell 20210120 2

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nucl ...[more]

PMID: 33470505

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Dataset Information

Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

Publications

Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

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